Pancreatic neuroendocrine tumors (PanNETs) are a group of rare tumors constituting 3% to 7% of all pancreatic neoplasms.[1–3] Most PanNETs are sporadic, and up to 90% are non-functioning. Even though non-functioning PanNETs (NFPanNETs) are defined as not producing hormones that cause symptoms, they may produce peptides such as ghrelin, chromogranin, and synaptophysin that can be detected in serum.
There is a slight male predilection in the incidence of NFPanNETs (crude annual incidence per 1000,000 is 1.8 in females and 2.6 in males) with the highest incidence between the 4th and 6th decade of life.[2,4,5] Several population-based analyses have demonstrated a rising trend in the incidence and prevalence of all neuroendocrine neoplasms as a whole, including PanNETs.[4–6] One review, for example, reported a 6.4-fold increase in the age-adjusted incidence of NETs between 1973 and 2012. Although the increased incidence was observed for all sites and stages of the disease, it was more marked in early-stage localized disease. This observation is believed to be due to the more widespread use of cross-sectional imaging.[5,12,13] Most primary tumors diagnosed in early stages are smaller compared to advanced stages and are usually asymptomatic; hence often diagnosed incidentally.[7–9] However, the heterogeneity in the behavior of PanNETs poses a unique challenge to treatment even in the early stages. The optimal treatment strategy for this cohort of patients has remained a source of debate.
Importantly, multiple population-level studies have shown improved overall survival (OS) for patients with PanNETs despite the relatively stable incidence of metastatic disease over several decades.[5–7] The causes for this observation are likely multifactorial and include the use of novel and effective systemic therapies, improved understanding and detection of neuroendocrine tumors, and perhaps the result of a more aggressive surgical strategy, even in the setting of advanced metastatic PanNETs.
In this review, we have identified 3 areas of controversies for the treatment of NFPanNETs, which we will aim to discuss:
- (1) Should all patients with small NFPanNETs equal or less than 2 cm in size be resected?
- (2) Should patients with metastatic NFPanNETs undergo surgical debulking?
- (3) Should the primary tumor be resected in the setting of unresectable metastatic disease?
Surgical treatment of non-functioning PanNETs
Surgical resection is the mainstay of treatment for all PanNETs and the only potential for a cure for localized tumors.[11,12,33,34] Several studies have demonstrated that enucleation of localized tumors has similar oncologic outcomes as anatomical resection.[15,68–70] Huttner et al published a meta-analysis of 22 studies (all of which were retrospective) including 1148 patients. They reported that enucleation improved operative time, operative blood loss, hospital length of stay, and postoperative endocrine and exocrine insufficiency. Also, they did not find any difference in the overall complication rate or overall mortality.
Should patients with small NFPanNETs ≤ 2 cm in size be resected?
Over the last decade, practice guidelines have considerably changed for the management of small NFPanNETs ≤ 2 cm. The unpredictable nature of these tumors, as well as the heterogeneity of data reported in the literature, makes this clinical scenario one of the most challenging aspects of care for these patients. Also, the mortality and morbidity of pancreatic resection are significant.[35–37] Therefore, the decision to resect an asymptomatic tumor should be carefully balanced against these risks as there is a danger of over-treatment. There are significant variations in the recommendations of older and more recent practice guidelines regarding the size cutoff for resection of small asymptomatic NFPanNETs. The 2010 North American Neuroendocrine Tumor Society (NANETS) guidelines recommended surgically removing all PanNETs as long as these are surgically resectable with acceptable surgical risks. The 2016 updated guidelines from the European Neuroendocrine Tumor Society (ENETS) recommended an individualized approach to these tumors (Fig. 1). In those guidelines, observation for patients with NFPanNETs < 2 cm is deemed appropriate as long as the patient is asymptomatic with a low tumor grade, and without radiological signs suggestive of malignancy (metastatic disease or enlarged peripancreatic lymph nodes [LNs]). The Canadian National Expert Group on Neuroendocrine tumors published similar guidelines shortly after ENETS. The most recent guidelines from the National Comprehensive Cancer Network (NCCN) recommend considering surgical resection for all tumors >1 cm in size regardless of their functional status and surveillance of patients with tumors <1 cm (Fig. 1). This approach is more aggressive and supported by the evolving data that demonstrate a survival advantage after resection and some degree of safety with the observation of patients with small NFPanNET < 1 cm and ≥1 cm, respectively (Fig. 2 and Table 1).
Of note, the updated 2019 NANETS guidelines for the management of NFPanNETs are currently in the press. It will recommend observation for patients with tumors <1 cm, and individualized treatment for patients with tumors 1 to 2 cm in size.
The heterogeneity of these guidelines reflects differences in reported outcomes of patients with small NFPanNETs. Sadot et al published a case-matched analysis of 181 PanNET patients with tumor <3 cm in size treated with either initial observation (104 patients) or surgical resection (77 patients) in a single institution. They found no difference in the OS between the 2 groups, although 25% of those who were initially observed crossed-over to resection after a median follow up of 30 months. There was no reported metastasis in the observed patients and no statistically significant changes in tumor size over the median follow-up of 44 months. Another striking finding from this study was that 95% of patients who had surgical resection had a low-grade tumor (G1), suggesting that even at 3 cm, the incidence of a high-grade tumor is <5%. While this is a single institution observational study, the findings are similar to those from other institutions.[38–41] These retrospective studies, despite their shortcomings, support the rationale to initially observe patients with small NFPanNETs in an effort to avoid morbid operations. This is especially true if the tumors are in the head of the pancreas, close to the main pancreatic duct or the common bile duct and thus may require a pancreaticoduodenectomy (PD) for complete resection. The limitations of these studies include their relatively short follow-up, retrospective design, and heterogeneity in the reporting and analysis of other factors that have been shown to affect prognosis (e.g., mitotic count).
Jutric et al analyzed 3 thousand patients in the National Cancer Database (NCDB) who underwent surgical resection for PanNETs. They reported a 51% incidence of LN metastasis in patients with PanNET in general, and in 24% incidence in patients with low-grade tumors that are <1 cm. The authors also reported an impact of LN positivity on overall median survival; 8 years for LN-positive and 11 years for LN-negative patients. This finding was similar to those found in SEER and other NCDB studies. Authors of all 3 studies therefore advocated for surgical resection of small NFPanNET, regardless of size. Similarly, Finkelstein et al performed a meta-analysis comparing surgical resection and observation for NFPanNET. They concluded that surgical resection was associated with a significant increase in OS, even for tumors ≤2 cm.
As noted above the NCCN's recommendations for small NFPanNETs are more aggressive, which are based in part on several studies that have demonstrated that surgical resection for tumors >1 cm confers a survival advantage compared to observation. In a recent NCDB analysis by Chivukula et al, 5-year OS for patients with NFPanNET ≤ 2 cm with or without LN metastasis was analyzed. They divided the patients into 3 separate categories; tumors <1 cm without LN metastasis, tumors 1 to 2 cm without LN metastasis, and tumors 2 cm or less with LN metastasis. They reported an increase in the 5-year OS in patients in all 3 groups who were resected compared to those observed, regardless of LN status. The significant survival difference in favor of surgical resection persisted for patients with tumors 1 to 2 cm but not in patients with 0 to 1 cm tumors after adjusting for confounders (age, tumor size, tumor grade, location of the tumor, and hospital type). They concluded that observation might be safe and appropriate for patients with tumors 0 to 1 cm. In comparison, they noted that those with tumors 1 to 2 cm in size would benefit from surgical resection.
There is currently no prospective data on this topic. However, most specialists tend to agree that observation is acceptable, as long as the patient agrees, the PanNET is non-functional, and less than 1 cm in size. Expert opinions differ significantly for larger tumors, and as reported above, there is limited data to make a final recommendation. In general, results from single institution studies and national cancer registries should be interpreted with caution since both study types have inherent biases. Frequent lack of complete information in registries may skew observations. In a recent systematic review and meta-analysis of the surveillance strategy for small NFPanNETs, comparing surgical resection to observation, Sallinen et al reported an overall low quality of published studies on the subject. The authors noted a low rate of diagnostic confirmation of NETs in patients in the observation arms as well as a significant variation in the indication for surgical resections in the surgical arms. Moreover, it also remains unclear how long to observe patients for and what the imaging interval between studies should comprise. More data, ideally prospective, is therefore needed to define which patients will benefit most from observation vs resection.
Should patients with metastatic NFPanNETs undergo surgical debulking?
Liver debulking surgery in this context refers to any cytoreductive surgical procedure aimed at reducing the overall neuroendocrine tumor burden in the liver, typically without a curative intent. Several studies have shown that the presence of LMs and tumor grade are some of the most important prognostic factors for PanNETs.[6,48–52] About 30% to 70% of patients present with distant metastases at the time of initial diagnosis, and most of these distant lesions are in the liver.[10,48] While some patients with stage IV disease will die of complications of their primary tumor or other reasons, a majority of patients with NFPanNETs will succumb to liver failure from overwhelming tumor burden.[6,25,53,54] Systemic therapies for well-or moderately differentiated metastatic PanNETs include long-acting octreotide analogs, chemotherapy (capecitabine and temozolomide), mammalian target of rapamycin, or vascular endothelial growth factor inhibition (everolimus or sunitinib) and radiotherapy with peptide receptor radionuclide therapy using Lutetium-177.[10,20–26] Even though most of these therapy options control the tumor burden for a certain amount of time, none of them have the potential to consistently lower tumor burden by inducing an objective response. Moreover, most prospective trials conducted for these therapies do not specifically assess their efficacy on metastatic liver tumor burden. Liver-directed therapies, in the form of transarterial embolization (with or without chemotherapy) and selective intra-arterial radiotherapy, have higher rates of objective response for liver tumor burden than systemic therapies. However, these response rates are rarely higher than 50%.[27,28,70–74] Also, none of these techniques treat the primary site or extrahepatic tumor burden. Surgical debulking, on the other hand, has the theoretical advantage of potentially removing or destroying all visible intraabdominal tumor sites and has been practiced for symptom control for decades. Whether surgical debulking can positively affect survival in patients with metastatic NFPanNETs remains a highly controversial topic.
The proponents of liver debulking postulate that the high rate of liver-failure related death in stage IV NET may be due to the inefficacy of the current systemic and liver-directed therapies and the underutilization of debulking liver surgery.[52,53] Moreover, some clinicians believe that systemic therapies can be more effective if a smaller tumor burden is present. Liver debulking surgery, therefore, is rarely curative for patients with metastatic PanNETs but instead dramatically diminishes tumor burden in most cases. Thus, debulking resets patients to an earlier time in their disease course, spreading out the time between usages of systemic therapies and, therefore, potentially improving patient survival.
Opponents of liver debulking surgery for metastatic PanNETs argue that recurrence after surgery for bilobar metastases is inevitable. They also posit that studies reporting the benefit of debulking surgery in NETs are retrospective and therefore compromised by patient selection bias. Also, they highlight the potential morbidities related to surgical intervention.
While there is no Level 1 evidence to guide surgical management in metastatic PanNET to the liver, a large number of retrospective studies from Europe and North America have demonstrated improvement in both symptom control and OS following debulking liver surgery in PanNET patients with LM.[17,62,63] A recent meta-analysis by Yu et al evaluated 13 cohort studies including 1524 patients with PanNET and LM. They showed that liver debulking surgery was associated with a significantly higher rate of symptom relief. They reported an improved 1-year (92.69% vs 77.31%), 3-year (76.93% vs 40.94%), and 5-year (67.54% vs 26.6%) OS rate compared to those who did not have a liver debulking surgery. The median OS was 84 (36–123) months in the group who had liver resection compared to 17 (17–54.8) months in the patients who did not have liver debulking surgery. The complication rate following liver debulking surgery in PanNETs, using parenchymal-sparing technique and microwave or radiofrequency ablation, range from 11% to 29% in experienced hands.[17,18]
Given the high incidence of synchronous presentation of PanNETs and LM, surgeons are often faced with the unique challenge of determining the optimal strategy of treating these patients. While there are no Level 1 data to guide therapy in this setting, some retrospective studies have evaluated the safety, benefit, and optimal surgical strategy in this scenario. Morgan et al, for example, evaluated patients who had distal pancreatectomy and liver debulking surgery concurrently or as staged procedures. They reported that there was no statistically significant difference in blood loss, transfusion requirement, length of hospital stay, and perioperative complications. Of note, most of the patients who had concurrent liver and pancreatic resection in this study were younger compared to those who had staged operations. This potential selection bias may have influenced the outcome of the study. Scott et al reported an 18-year outcome (safety and efficacy) of 188 liver debulking surgeries for patients with PanNET and LM. A majority of the patients in the study (74%) had combined liver and pancreatic resections. A significant number received octreotide analog therapy—64% pre-operatively and 97% postoperatively. They reported that there was no difference in the complication rate (15% rate of major complication), progression-free survival (median 22.5 months) or OS (median of 89 months from time of resection and 154 months from time of diagnosis) regardless of the sequence of operation or number of lesions removed. They concluded that extensive surgical debulking could be achieved with acceptable safety and comparable survival indices. These findings are consistent with other studies reporting on the surgical outcome of liver debulking.[17,18,44,58,65]
It is important to note that several studies have reported a higher perioperative complication rate in patients undergoing synchronous PD and debulking liver surgery. It is hypothesized that since a hepaticojejunostomy allows for bacterial translocation into the liver via the biliary tree, increased rates of intrahepatic abscesses can occur. De Jong et al analyzed the outcome of 5025 patients who underwent PD, of which 129 patients had a concurrent resection of pancreatic tumor and metastatic liver lesion in either a synchronized (45%) or a staged (55%) fashion. The authors found that liver abscess formation was higher in patients undergoing any staged resection (14.5%) or synchronous resection (7%) when compared to those patients undergoing PD alone.
The current NCCN guidelines also recommend that surgical liver debulking should occur before pancreatic resection in a staged operation, to decrease the risk of perihepatic sepsis or abscess.
Historically, surgeons have adopted the idea that surgical liver debulking should only be performed if resection of at least 90% of the tumor burden is feasible. Some clinical practice guidelines have incorporated the 90% target in their recommendation.[29,55] However, there are potential problems with adopting a 90% threshold. First, there is no comparative effectiveness analysis of the optimal threshold for liver debulking surgery that confers more benefit and less risk in a patient with metastatic PanNETs or any NET subtypes for that matter. The adoption of the 90% target resulted from experience and report of earlier retrospective studies from single institutions and a relatively small number of patients, some from over 35 years ago.[55–57] Second, given that a significant number of PanNET patients present with multiple bilobar LMs, many patients will be denied potentially beneficial therapy. Most studies supporting the >90% resection threshold report that only 25% of patients presenting with PanNETs and LM are eligible for resection.[62,67] However, most recent studies have shown increased eligibility of up to 84% by lowering the resection target to 70% with no difference in OS.[62,63,65,66] Earlier investigators perceived surgical resectability as a resection that allows adequate surgical margin. However, several recent studies have demonstrated that while margin status may affect progression-free survival, it does not affect the OS of patients with NFPanNETs.[44,58–60] Lastly, the pre-operative liver tumor burden that reliably translates into a certain debulking threshold remains unknown. At our institution, we generally use a total liver tumor burden (as calculated by 2-dimensional measurements of each lesion) of 25% as an acceptable threshold to repeatedly achieve 90% debulking. (Table 1 and Fig. 2)
There are no prospective data on the controversial subject of liver debulking in NFPanNETs. However, it would be challenging to perform a prospective randomized study evaluating surgical debulking vs other therapies or observations in patients with metastatic NFPanNETs. This challenge would stem from the rarity of this disease (requiring a multicentre approach) and the heterogeneity in resection techniques and experience. There would be a potential difficulty with accrual to a non-resection arm, as most patients will choose surgery when offered. Therefore, prospective evaluation of the combined effect of liver debulking surgery and other systemic therapies may add significant knowledge to this treatment approach and better define the role for this therapeutic intervention in the future.
Should the primary tumor be resected in the setting of non-resectable metastatic disease?
Historically, patients with unresectable distant disease and primary PanNETs were thought to derive benefit from surgical resection of their primary tumor only if they were symptomatic. This is reflected in the ENETS guidelines, which recommend resection in this clinical scenario to forestall life-threatening complications resulting from the location of the tumor such as hemorrhage, acute pancreatitis, jaundice, and bowel obstruction. Despite this suggestion, some patients have undergone resection of their primary tumor in the setting of unresectable metastatic disease, as reported in multiple large database studies.[30,31,66] Tierney et al evaluated the outcomes of 6548 patients with metastatic gastroenteropancreatic NET at diagnosis entered in the NCDB between 2004 and 2014. 7.6% of the 6548 patients had PanNET. Patients with PanNETs who underwent resection of their primary tumor demonstrated a statistically significant increase in the median OS; 63.6 vs 14.2 months in those who did not undergo resection. Similar findings were also reported in a study from the SEER database analyzing 882 patients with NFPanNETs. It should be noted that both the NCDB and SEER database study showed that resection rates were significantly higher in patients with tumors in the pancreatic body or tail, reflecting most surgeons’ willingness to perform an operation with less morbidity in this special circumstance.
A recent systematic review and meta-analysis by Zhou et al, which included 10 studies with a total of 2489 patients with PanNET and unresectable LM, showed that palliative resection of the primary tumor can increase OS. In this study, there was a statistically significant difference in the 5-year OS rate (between 35.7% and 83%) in patients who had resection of their primary pancreatic tumor compared to the patients who did not have resection of their primary tumor (between 5.4% and 50%). Of note, there was some bias towards patients with better performance status, less advanced disease and whose tumors were not in the head of the pancreas. Perhaps the most convincing study demonstrating a benefit from primary tumor resection in this setting was performed by Lewis et al. They utilized the California Cancer Registry dataset merged with California Office of State-wide Health Planning and Development to identify 854 patients with gastrointestinal and pancreatic NET metastases of which 392 patients underwent primary tumor resection. On multivariate analysis adjusted for demographics, tumor stage, grade, chemotherapy use, Charlson comorbidity index, primary tumor location, or treatment of LMs, primary tumor resection, irrespective of liver treatment, improved OS in comparison to no resection (hazard ratio 0.50, P < .001 and .39, P < .001, respectively).
These data again suggest that surgical therapy should further be studied in combination with systemic therapies in order to determine if and how either therapeutic approach might influence and improve the other.
In conclusion, surgical therapy for PanNETs has the potential to cure patients, but certain aspects remain highly controversial. This is mostly due to the retrospective nature of most surgical studies in this domain. Despite these limitations, tremendous advances have been made in understanding the indication and timing of resection of these tumors.
Further improvement will almost certainly continue as long as surgeons remain an integral part of the decision-making process when treating PanNETs with localized or metastatic disease.
Conflicts of interest
The authors declare no conflicts of interest.
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